Cancer and Antibody therapies
Cancer is among the top killer diseases in our society today. According to World Cancer Report 2014, about 14.1 million new cancer cases occur every year, not including skin cancer other than melanoma. Cancers caused about 8.8 million deaths a year (GBL) 2015 Disease and Injury Incidence and Prevalence Collaborators, (2016) Lancet 388 (10053):1545-1602). For example, gastric cancer is the fourth (in males) and fifth (in females) most common causes of cancer-related deaths in the developed countries.
Many cancers, especially those at an advanced stage, remain difficult to cure. For example, the overall five-year survival rate for gastroesophageal cancer is only 20-25%, despite the aggressiveness of the current standard treatment, itself associated with substantial side effects. For pancreatic cancer, patients are usually diagnosed at an advanced stage, so the prognosis is extremely poor, where the median survival time is less than 6 months, and the 5-year survival rate is less than 5.5%.
Antibody therapies are approved in various jurisdictions to treat a wide range of cancers, and have significantly improved patient outcomes (Komeev et al., (2017) Cytokine 89: 127-135). Once bound to a cancer antigen, antibodies may induce antibody-dependent cell-mediated cytotoxicity, activate the complement system, or prevent a receptor from interacting with its ligand, all of which can lead to cancer cell deaths. U.S. FDA-approved antibody drugs include Alemtuzumab, Nivolumab, Rituximab and Durvalumab.
Claudin 18.2
Claudins, first reported by Shorichiro Tsukita et al. in 1998 (Furuse et al., (1998) J Cell Biol 141(7): 1539-1550), are a family of cell-surface proteins that establish a paracellular barrier and control the flow of molecules between cells (Singh et al., (2010) J Oncol 2010: 541957). Claudins are integral components of tight junctions that play important roles in maintaining epithelial cell polarity, controlling paracellular diffusion, and regulating cell growth and differentiation. The other two main tight junction family proteins are occludin and junctional adhesion molecule (JAM). Each claudin molecule spans the cellular membrane 4 times, with the N-terminal and C-terminal ends both located in the cytoplasm.
By now 24 claudin members have been reported in mammals, with Claudin 13 missing in humans. Different claudin members are expressed on different tissues, and their altered functions have been linked to the formation of cancers. Claudin 1, Claudin 18 and Claudin 10 expression level changes have been associated with colon cancer, gastric cancer and hepatocellular carcinoma, respectively, and claudins have thus become promising targets for therapeutic strategies (Swisshelm et al., (2005) Adv Drug Deliv Rev 57(6): 919-928).
Claudin 18, also known as CLD18, has two isoforms. Claudin 18.1 is selectively expressed on normal lung and stomach epithelia. Claudin 18.2 also has a highly restricted expression pattern in normal tissues, limited on the differentiated short-lived cells of stomach epithelium only, and notably absent in the gastric stem cells zone.
Claudin 18.2, however, is abundant in a significant proportion of primary gastric cancers and its metastases, and plays an important role in their malignant transformation. For example, frequent ectopic activation of claudin 18.2 was found in pancreatic, esophageal, ovarian, and lung tumors (Niimi et al., (2001) Mol Cell Biol 21(21): 7380-7390; Tanaka et al. (2011) J Histochem Cytochem 59(10): 942-952; Micke et al., (2014) Int J Cancer 135(9): 2206-2214; Shimobaba et al. (2016) Biochim Biophys Acta 1863(6 Pt A): 1170-1178; Singh et al., (2017) J Hematol Oncol 10(1): 105; Tokumitsu et al., (2017) Cytopathology 28(2): 116-121).
Claudin 18.2 has exposed extracellular loops available for monoclonal antibody binding, and CLDN18.2 antibodies have been used in studies to treat cancers. For example, Claudiximab (IMAB362), a chimeric anti-Claudin 18.2 IgG1 antibody developed by Ganymed, has shown encouraging efficacies in phase 1 and phase 2 clinical trials for treating advanced gastroesophageal cancers (Sahin et al., (2018) Eur J Cancer 100: 17-26).
With the unmet medical needs in many malignancies, there is a need for additional anti-Claudin 18.2 monoclonal antibodies with more desirable pharmaceutical characteristics.